Taxoids, their preparation and pharmaceutical compositions containing them

ABSTRACT

This invention relates to taxoids of the formula (I):  a method for preparing these taxoids, and pharmaceutical compositions containing them. In formula (I), R is alkyl radical (1-6 carbon atoms), alkenyl (2-6 carbon atoms), alkynyl (2-6 carbon atoms), cycloalkyl (3-6 carbon atoms), cycloalkenyl (4-6 carbon atoms), phenyl, unsaturated heterocyclyl containing from 5 to 6 links, Z is a hydrogen atom or a radical of formula (II): ##STR1## wherein R 1  is an optionally substituted benzoyl radical, thenoyl radical, furoyl radical, or a radical R 2  --O--CO-- in which R 2  is an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, optionally substituted phenyl or heterocyclyl, and R 3  is an alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, naphthyl or aromatic heterocyclic radical. The taxoids of formula (I) in which Z is a radical of formula (II) have remarkable antitumoral and antileukemic properties.

This is a 371 application of PCT/FR95/00736 dated Jun. 7, 1995,published as WO95/33737, Dec. 14, 1995.

The present invention relates to relates to new taxoids of generalformula: ##STR2## in which: R represents an unbranched or branched alkylradical containing 1 to 6 carbon atoms, an unbranched or branchedalkenyl radical containing 2 to 6 carbon atoms, an unbranched orbranched alkynyl radical containing 2 to 6 carbon atoms, a cycloalkylradical containing 3 to 6 carbon atoms, a cycloalkenyl radicalcontaining 4 to 6 carbon atoms, an aryl radical or a 5- to 6-memberedaromatic heterocyclic radical,

Z represents a hydrogen atom or a radical of general formula: ##STR3##in which: R₁ represents a benzoyl radical optionally substituted withone or more identical or different atoms or radicals chosen from halogenatoms and alkyl radicals containing 1 to 4 carbon atoms, alkoxy radicalscontaining 1 to 4 carbon atoms or trifluoromethyl radicals, a thenoyl orfuroyl radical or a radical R₂ --O--CO-- in which R₂ represents:

an alkyl radical containing 1 to 8 carbon atoms, an alkenyl radicalcontaining 2 to 8 carbon atoms, an alkynyl radical containing 3 to 8carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms, acycloalkenyl radical containing 4 to 6 carbon atoms or a bicycloalkylradical containing 7 to 10 carbon atoms, these radicals being optionallysubstituted with one or more substituents chosen from halogen atoms andhydroxyl radicals, alkoxy radicals containing 1 to 4 carbon atoms,dialkylamino radicals in which each alkyl portion contains 1 to 4 carbonatoms, piperidino or morpholino radicals, 1-piperazinyl radicals(optionally substituted at position 4 with an alkyl radical containing 1to 4 carbon atoms or with a phenylalkyl radical in which the alkylportion contains 1 to 4 carbon atoms), cycloalkyl radicals containing 3to 6 carbon atoms, cycloalkenyl radicals containing 4 to 6 carbon atoms,phenyl radicals (optionally substituted with one or more atoms orradicals chosen from halogen atoms and alkyl radicals containing 1 to 4carbon atoms or alkoxy radicals containing 1 to 4 carbon atoms), cyanoor carboxyl radicals or alkoxycarbonyl radicals in which the alkylportion contains 1 to 4 carbon atoms,

a phenyl or α- or β-naphthyl radical optionally substituted with one ormore atoms or radicals chosen from halogen atoms and alkyl radicalscontaining 1 to 4 carbon atoms or alkoxy radicals containing 1 to 4carbon atoms, or a 5-membered aromatic heterocyclic radical preferablychosen from furyl and thienyl radicals,

or a saturated heterocyclic radical containing 4 to 6 carbon atoms,optionally substituted with one or more alkyl radicals containing 1 to 4carbon atoms,

R₃ represents an unbranched or branched alkyl radical containing 1 to 8carbon atoms, an unbranched or branched alkenyl radical containing 2 to8 carbon atoms, an unbranched or branched alkynyl radical containing 2to 8 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms,a phenyl or α- or β-naphthyl radical optionally substituted with one ormore atoms or radicals chosen from halogen atoms and alkyl, alkenyl,alkynyl, aryl, aralkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxyl,hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino,alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxyl,alkoxycarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano,nitro and trifluoromethyl radicals, or a 5-membered aromatic heterocyclecontaining one or more identical or different hetero atoms chosen fromnitrogen, oxygen and sulphur atoms and optionally substituted with oneor more identical or different substituents chosen from halogen atomsand alkyl, aryl, amino, alkylamino, dialkylamino, alkoxycarbonylamino,acyl, arylcarbonyl, cyano, carboxyl, carbamoyl, alkylcarbamoyl,dialkylcarbamoyl or alkoxycarbonyl radicals, on the understanding that,in the substituents of the phenyl, α- or β-naphthyl and aromatichetereocyclic radicals, the alkyl radicals and the alkyl portions of theother radicals contain 1 to 4 carbon atoms, and that the alkenyl andalkynyl radicals contain 2 to 8 carbon atoms, and that the aryl radicalsare phenyl or α- or β-naphthyl radicals.

Preferably, the aryl radicals which can be represented by R and R₃ arephenyl or α- or β-naphthyl radicals optionally substituted with one ormore atoms or radicals chosen from halogen atoms (fluorine, chlorine,bromine, iodine) and alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkoxy,alkylthio, aryloxy, arylthio, hydroxyl, hydroxyalkyl, mercapto, formyl,acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino,dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl, dialkylcarbamoyl,cyano, nitro and trifluoromethyl radicals, on the understanding that thealkyl radicals and the alkyl portions of the other radicals contain 1 to4 carbon atoms, that the alkenyl and alkynyl radicals contain 2 to 8carbon atoms and that the aryl radicals are phenyl or α- or β-naphthylradicals.

Preferably, the heterocyclic radicals which can be represented by R andR₃ are 5-membered aromatic heterocyclic radicals containing one or moreidentical or different atoms chosen from nitrogen, oxygen and sulphuratoms, optionally substituted with one or more identical or differentsubstituents chosen from halogen atoms (fluorine, chlorine, bromine,iodine) and alkyl radicals containing 1 to 4 carbon atoms, aryl radicalscontaining 6 to 10 carbon atoms, alkoxy radicals containing 1 to 4carbon atoms, aryloxy radicals containing 6 to 10 carbon atoms, aminoradicals, alkylamino radicals containing 1 to 4 carbon atoms,dialkylamino radicals in which each alkyl portion contains 1 to 4 carbonatoms, acylamino radicals in which the acyl portion contains 1 to 4carbon atoms, alkoxycarbonylamino radicals containing 1 to 4 carbonatoms, acyl radicals containing 1 to 4 carbon atoms, arylcarbonylradicals in which the aryl portion contains 6 to 10 carbon atoms, cyano,carboxyl or carbamoyl radicals, alkylcarbamoyl radicals in which thealkyl portion contains 1 to 4 carbon atoms, dialkylcarbamoyl radicals inwhich each alkyl portion contains 1 to 4 carbon atoms or alkoxycarbonylradicals in which the alkoxy portion contains 1 to 4 carbon atoms.

More especially, the present invention relates to the products ofgeneral formula (I) in which R represents an alkyl radical containing 1to 4 carbon atoms, Z represents a hydrogen atom or a radical of generalformula (II) in which R₁ represents a benzoyl radical or a radical R₂--O--CO-- in which R₂ represents a tert-butyl radical and R₃ representsan alkyl radical containing 1 to 6 carbon atoms, an alkenyl radicalcontaining 2 to 6 carbon atoms, a cycloalkyl radical containing 3 to 6carbon atoms, a phenyl radical optionally substituted with one or moreidentical or different atoms or radicals chosen from halogen atoms(fluorine, chlorine) and alkyl (methyl), alkoxy (methoxy), dialkylamino(dimethylamino), acylamino (acetylamino), alkoxycarbonylamino(tert-butoxycarbonylamino) or trifluoromethyl radicals, or a 2- or3-furyl, 2- or 3-thienyl or 2-, 4- or 5-thiazolyl radical.

Still more especially, the present invention relates to the products ofgeneral formula (I) in which R represents a methyl radical, Z representsa hydrogen atom or a radical of general formula (II) in which R₁represents a benzoyl radical or a radical R₂ --O--CO-- in which R₂represents a tert-butyl radical and R₃ represents an isobutyl,isobutenyl, butenyl, cyclohexyl, phenyl, 2-furyl, 3-furyl, 2-thienyl,3-thienyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl radical.

The products of general formula (I) in which Z represents a radical ofgeneral formula (II) display noteworthy antitumour and antileukaemicproperties.

According to the present invention, the products of general formula (I)in which R and Z are defined as above may be obtained by the action ofan organometallic derivative of general formula:

    R--X                                                       (III)

in which R is defined as above and X represents a metal atom such as alithium atom or an organomagnesium residue (Mg--Y in which Y representsa halogen atom), on a product of general formula: ##STR4## in which Z₁represents a hydrogen atom or a radical of general formula: ##STR5## inwhich R₁ and R₃ are defined as above, and either R₄ represents ahydrogen atom and R₅ represents a group protecting the hydroxylfunction, or R₄ and R₅ together form a heterocycle, to obtain a productof general formula: ##STR6## followed, where appropriate, by replacementof the protective groups represented by R₅ of/or R₄ and R₅ and the Zmolety by hydrogen atoms.

Generally, the process is carried out in an inert organic solvent suchas an ether (tetrahydrofuran) at a temperature of between -78° and 30°C.

Preferably, R₄ represents a hydrogen atom and R₅ represents a groupprotecting the hydroxyl function, or alternatively R₄ and R₅ togetherform a 5- or 6-membered saturated heterocycle.

When R₄ represents a hydrogen atom, R₅ preferably represents amethoxymethyl, 1-ethoxyethyl, benzyloxymethyl, trimethylsilyl,triethylsilyl, β-trimethylsilyloxymethyl, benzyloxycarbonyl ortetrahydropyranyl radical.

When R₄ and R₅ together form a heterocycle, the latter is preferably anoxazolidine ring optionally monosubstituted or gem-disubstituted atposition 2.

Replacement of the protective groups R₅ and/or R₄ and R₅ by hydrogenatoms may be performed, depending on their nature, in the followingmanner:

1) when R₄ represents a hydrogen atom and R₅ represents a groupprotecting the hydroxyl function, replacement of the protective groupsby hydrogen atoms is performed by means of an inorganic acid(hydrochloric acid, sulphuric acid, hydrofluoric acid) or organic acid(acetic acid, methanesulphonic acid, trifluoromethanesulphonic acid,p-toluenesulphonic acid) used alone or mixed, working in an organicsolvent chosen from alcohols, ethers, esters, aliphatic hydrocarbons,halogenated aliphatic hydrocarbons, aromatic hydrocarbons or nitriles ata temperature of between -10° and 60° C.,

2) when R₄ and R₅ together form a 5- or 6-membered saturatedheterocycle, and more especially an oxazolidine ring of general formula:##STR7## in which R₁ is defined as above and R₆ and R₇, which may beidentical or different, represent a hydrogen atom or an alkyl radicalcontaining 1 to 4 carbon atoms, or an aralkyl radical in which the alkylportion contains 1 to 4 carbon atoms and the aryl portion preferablyrepresents a phenyl radical optionally substituted with one or morealkoxy radicals containing 1 to 4 carbon atoms, or an aryl radicalpreferably representing a phenyl radical optionally substituted with oneor more alkoxy radicals containing 1 to 4 carbon atoms, or alternativelyR₆ represents an alkoxy radical containing 1 to 4 carbon atoms or atrihalomethyl radical such as trichloromethyl or a phenyl radicalsubstituted with a trihalomethyl radical such as trichloromethyl and R₇represents a hydrogen atom, or alternatively R₆ and R₇, together withthe carbon atom to which they are attached, form a 4- to 7-memberedring, replacement of the protective group formed by R₆ and R₇ byhydrogen atoms may be performed, depending on the meanings of R₁, R₆ andR₇, in the following manner:

a) when R₁ represents a tert-butoxycarbonyl radical and R₆ and R₇, whichmay be identical or different, represent an alkyl radical or an aralkyl(benzyl) or aryl (phenyl) radical, or alternatively R₆ represents atrihalomethyl radical or a phenyl radical substituted with atrihalomethyl radical and R₇ represents a hydrogen atom, oralternatively R₆ and R₇ together form a 4- to 7-membered ring, treatmentof the ester of general formula (VI) with an inorganic or organic acid,where appropriate in an organic solvent such as an alcohol, yields theproduct of general formula: ##STR8## in which R and R₃ are defined asabove, which is acylated by means of benzoyl chloride in which thephenyl ring is optionally substituted or by means of thenoyl chloride,of furoyl chloride or of a product of general formula:

    R.sub.2 --O--CO--X                                         (IX)

in which R₂ is defined as above and X represents a halogen atom(fluorine, chlorine) or a residue --O--R₂ or --O--CO--O--R₂, to obtain aproduct of general formula (I) in which Z represents a radical ofgeneral formula (II).

Preferably the product of general formula (VI) is treated with formicacid at a temperature in the region of 20° C.

Preferably, the acylation of the product of general formula (VIII) bymeans of a benzoyl chloride in which the phenyl radical is optionallysubstituted or by means of thenoyl chloride, of furoyl chloride or of aproduct of general formula (IX) is performed in an inert organic solventchosen from esters such as ethyl acetate, isopropyl acetate or n-butylacetate and halogenated aliphatic hydrocarbons such as dichloromethaneor 1,2-dichloroethane, in the presence of an inorganic base such assodium bicarbonate or an organic base such as triethylamine. Thereaction is performed at a temperature of between 0° and 50° C., andpreferably in the region of 20° C.

b) when R₁ represents an optionally substituted benzoyl radical, athenoyl or furoyl radical or a radical R₂ O--CO-- in which R₂ is definedas above, R₆ represents a hydrogen atom or an alkoxy radical containing1 to 4 carbon atoms or a phenyl radical substituted with one or morealkoxy radicals containing 1 to 4 carbon atoms and R₇ represents ahydrogen atom, replacement of the protective group formed by R₆ and R₇by hydrogen atoms is performed in the presence of an inorganic acid(hydrochloric acid, sulphuric acid) or organic acid (acetic acid,methanesulphonic acid, trifluoromethanesulphonic acid,p-toluenesulphonic acid) used alone or mixed in a stoichiometric orcatalytic amount, working in an organic solvent chosen from alcohols,ethers, esters, aliphatic hydrocarbons, halogenated aliphatichydrocarbons and aromatic hydrocarbons at a temperature of between -10°and 60° C., and preferably between 15° and 30° C.

The product of general formula (IV) may be obtained by oxidation of aproduct of general formula: ##STR9## in which Z₁ is defined as above.

Generally, the oxidation is carried out by means of an oxidizing agentpreferably chosen from pyridinium chlorochromate, pyridinium dichromate,potassium dichromate, ammonium dichromate, pyridinium dichromate ormanganese dioxide, under conditions which do not affect the remainder ofthe molecule.

Depending on the nature of the oxidizing agent used, the oxidation iscarried out in an anhydrous organic medium or in an aqueous-organicmedium.

Generally, the oxidation is carried out at a temperature of between 0°and 50° C.

The products of general formula (X) may be obtained by the action of analkali metal halide (sodium chloride, sodium iodide, potassium fluoride)or an alkali metal azide (sodium azide) or a quaternary ammonium salt oran alkali metal phosphate on a baccatin III or 10-deacetylbaccatin IIIderivative of general formula: ##STR10## in which Z₁ is defined asabove.

Generally, the reaction is performed in an organic solvent chosen fromethers (tetrahydrofuran, diisopropyl ether, methyl t-butyl ether) andnitriles (acetonitrile), alone or mixed, at a temperature between 20° C.and the boiling point of the reaction mixture.

The product of general formula (XI) may be obtained by the action by theaction of a trifluoromethanesulphonic acid derivative such as theanhydride or N-phenyltrifluoromethanesulphonimide on a product ofgeneral formula: ##STR11## in which Z₁ is defined as above.

Generally, the reaction is performed in an inert organic solvent(aliphatic hydrocarbons, optionally halogenated, aromatic hydrocarbons)in the presence of an organic base such as a tertiary aliphatic amine(triethylamine) or pyridine at a temperature of between -50° and +20° C.

The products of general formula (XII) may be prepared under theconditions described in European Patents EP 0,253,738 or EP 0,336,841 orin PCT International Application WO 92/09589 the disclosure of which arehereby incorporated by reference.

The new products of general formula (I) obtained by carrying out theprocesses according to the invention may be purified according to knownmethods such as crystallization or chromatography.

The products of general formula (I) in which Z represents a radical ofgeneral formula (II) display noteworthy biological properties.

In vitro, measurement of the biological activity is performed on tubulinextracted from pig's brain by the method of M. L. Shelanski et al.,Proc. Natl. Acad. Sci. USA, 70, 765-768 (1973). Study of thedepolymerization of microtubules to tubulin is performed according tothe method of G. Chauviere et al., C. R. Acad. Sci., 293, series II,501-503 (1981). In this study, the products of general formula (I) inwhich Z represents a radical of general formula (II) was shown to be atleast as active as taxol and Taxotere.

In vivo, the products of general formula (I) in which Z represents aradical of general formula (II) were shown to be active in mice graftedwith B16 melanoma at doses of between 1 and 10 mg/kg administeredintraperitoneally, as well as on other liquid or solid tumours.

The new products have antitumour properties, and more especiallyactivity against tumours which are resistant to Taxol® or to Taxotere®.Such tumours comprise colon tumours which have a high expression of themdr 1 gene (multiple drug resistance gene). Multiple drug resistance isa customary term relating to the resistance of a tumour to differentproducts having different structures and mechanisms of action. Taxoidsare generally known to be strongly recognized by experimental tumourssuch as P388/DOX, a cell line selected for its resistance to doxorubicin(DOX) which expresses mdr 1.

The examples which follow illustrate the present invention.

EXAMPLE 1

0.116 cm³ of a 3M solution of methylmagnesium iodide in ethyl ether isadded dropwise to a solution, maintained under an argon atmosphere at atemperature in the region of -78° C., of 260 mg of 4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β-hydroxy-7,8β-methylene-9,10-dioxo-19-nor-11-taxen-13α-yl(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylatein 5 cm³ of tetrahydrofuran. After 75 minutes at -78° C., a further0.116 cm³ of a 3M solution of methylmagnesium iodide in ethyl ether isadded dropwise. The reaction mixture is stirred for 30 minutes at -78°C. and then for 18 hours at a temperature in the region of 0° C. Aftercooling to a temperature in the region of -78° C., 0.116 cm³ of a 3Msolution of methylmagnesium iodide in ethyl ether is added dropwise andthe mixture is then allowed to react for 20 minutes at -78° C., for 30minutes at 0° C. and then for 30 minutes at 20° C. The reaction mixtureis treated with 1 cm³ of saturated aqueous ammonium chloride solutionand 5 cm³ of ethyl acetate. After settling has taken place, the aqueousphase is separated and extracted with 1.5 cm³ of ethyl acetate, and theorganic phases are combined, dried over magnesium sulphate, filteredthrough sintered glass and concentrated under reduced pressure (0.27kPa) at a temperature in the region of 40° C. 240 mg of anorange-coloured foam are thereby obtained, which product is purified bychromatography at atmospheric pressure on 10 g of silica (0.063-0.2 mm)contained in a column 1.6 cm in diameter (eluent:methanol/dichloromethane, 3:97 by volume), collecting 5 cm³ fractions.Fractions containing only the desired product are pooled andconcentrated to dryness under reduced pressure (0.27 kPa) at 40° C. for2 hours. 0.15 g of4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,10β-dihydroxy-10α-methyl-7,8β-methylene-9-oxo-19-nor-11-taxen-13α-yl(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylateis thereby obtained in the form of a bright yellow foam.

A solution of 75 mg of4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,10β-dihydroxy-10α-methyl-7,8β-methylene-9-oxo-19-nor-11-taxen-13α-yl(2R,4S,4R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylatein 1.5 cm³ of a 0.1N solution of hydrochloric acid in ethanol is stirredat a temperature in the region of 20° C. for 5 hours. A further 0.5 cm³of 0.1N hydrochloric acid in ethanol is added. After 16 hours at atemperature in the region of 5° C., a further 0.5 cm³ of 0.1Nhydrochloric acid in ethanol is added and the solution is stirred for afurther 3 hours at a temperature in the region of 20° C. The reactionmixture is diluted with 2.5 cm³ of dichloromethane, 2.5 cm³ of saturatedaqueous sodium hydrogen carbonate solution and 2 cm³ of distilled water.After settling has taken place, the aqueous phase is separated andextracted with 5 cm³ of dichloromethane, and the organic phases arecombined, dried over magnesium sulphate, filtered through sintered glassand concentrated under reduced pressure (0.27 kPa) at a temperature inthe region of 40° C. 124 mg of a yellow foam are thereby obtained, whichproduct is purified by preparative thin-layer chromatography 5 Merckpreparative plates, Silica gel 60F₂₅₄, thickness 0.5 mm, application insolution in dichloromethane, eluent: methanol/dichloromethane (5:95 byvolume) mixture!. After elution of the zone corresponding to the majorproduct with a methanol/dichloromethane (10:90 by volume) mixture,filtration through sintered glass and then evaporation of the solventsunder reduced pressure (0.27 kPa) at a temperature in the region of 40°C., 37 mg of4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,10β-dihydroxy-10α-methyl-7,8β-methylene-9-oxo-19-nor-11-taxen-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate areobtained in the form of a white foam, the characteristics of which areas follows:

¹ H NMR spectrum (600 MHz, CDCl₃, δ in ppm): 1.21 (s, 3H:CH₃); 1.22 (s,9H:C(CH₃)₃); 1.28 (s, 3H:CH₃); 1.38 (mt, 1H:H at position 7); 1.68 and2.31 (2 mt, 1H each:CH₂ at position 19); 1.70 (s, 3H:CH₃ at position10); 1.85 (s, 1H:OH at position 1); 1.87 (s, 3H:CH₃); 2.17 and 2.33 (2mt, 1H each:CH₂ at position 14); 2.17 and 2.43 (respectively d and dt,J=16 and J=16 and 4.5 Hz, 1H each:CH₂ at position 6); 2.41 (s,3H:COCH₃); 3.25 (mt, 1H:OH at position 2'); 4.05 and 4.35 (2d, J=9 Hz,1H each:CH₂ at position 20); 4.30 (d, J=7 Hz, 1H:H at position 3); 4.42(s, 1H:OH at position 10); 4.60 (mt, 1H:H at position 2'); 4.75 (d, J=4Hz, 1H:H at position 5); 5.30 (mt, 1H:H at position 3'); 5.38 (d, J=10Hz, 1H:CONH); 5.67 (d, J=7 Hz, 1H:H at position 2); 6.33 (broad t, J=9Hz, 1H:H at position 13); 7.30 (t, J=7.5 Hz, 1H:aromatic at position 3'H at para position); 7.37 (d, J=7.5 Hz, 2H:aromatic at position 3' H atortho position); 7.40 (t, J=7.5 Hz, 2H:aromatic at position 3' H at metaposition); 7.51 (t, J=7.5 Hz, 2H:OCOC₆ H₅ H at meta position); 7.60 (t,J=7.5 Hz, 1H:OCOC₆ H₅ H at para position); 8.17 (d, J=7.5 Hz, 2H:OCOC₆H₅ H at ortho position).

4α-Acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,-hydroxy-7,8.beta.-methylene-9,10-dioxo-19-nor-11-taxen-13α-yl(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylatemay be prepared in the following manner:

0.5 g of 4 Å molecular sieve is added to a solution, maintained under anargon atmosphere at a temperature in the region of 20° C., of 900 mg of4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,10β-dihydroxy-7,8β-methylene-9-oxo-19-nor-11-taxen-13α-yl(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylatein 9 cm³ of dichloromethane, and 0.43 g of pyridinium chlorochromate isthen added portionwise under the same conditions. The reaction mixtureis stirred for 90 minutes at a temperature in the region of 20° C. andthen filtered through sintered glass lined with Clarcel. After the solidresidue is rinsed with dichloromethane, the filtrates are concentratedunder reduced pressure (0.27 kPa) at a temperature in the region of 40°C. 1.13 g of a brown resin are thereby obtained, which product ispurified by chromatography at atmospheric pressure on 40 g of silica(0.063-0.2 mm) contained in a column 2.2 cm in diameter (eluent:methanol/dichloromethane, 2:98 by volume), collecting 10 cm³ fractions.Fractions containing only the desired product are pooled andconcentrated to dryness under reduced pressure (0.27 kPa) at 40° C. for2 hours. 0.63 g of4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β-hydroxy-7,8.beta.-methylene-9,10-dioxo-19-nor-11-taxen-13α-yl(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylateis thereby obtained in the form of a yellow-green foam.

4α-Acetoxy-2αbenzoyloxy-5β,20-epoxy-1β,10-dihydroxy-7,8β-methylene-9-oxo-19-nor-11-taxen-13α-yl(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylatemay be prepared in the following manner:

1.5 g of sodium chloride and 0.5 g of 4 Å molecular sieve is added to asolution of 1.8 g4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,10β-dihydroxy-9-oxo-7β-trifluoromethanesulphonyloxy-11-taxen-13α-yl(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylatein 20 cm³ of acetonitrile and 3 cm³ of tetrahydrofuran. The reactionmixture is brought to reflux under an inert argon atmosphere for 1 hour,brought back to a temperature in the region of 20° C. and filteredthrough sintered glass. The solid residue is rinsed with 10 cm³ of ethylacetate. The filtrates are combined, dried over magnesium sulphate,filtered through sintered glass and concentrated under reduced pressure(0.27 kPa) at a temperature in the region of 40° C. 1.6 g of a yellowfoam are thereby obtained, which product is purified by chromatographyat atmospheric pressure on 60 g of silica (0.063-0.2 mm) contained in acolumn 3 cm in diameter (eluent: ethyl acetate/dichloromethane, 20:80 byvolume), collecting 10 cm³ fractions. Fractions containing only thedesired product are pooled and concentrated to dryness under reducedpressure (0.27 kPa) at 40° C. for 2 hours. 0.91 g of4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,10β-dihydroxy-7,8β-methylene-9-oxo-19-nor-11-taxen-13α-yl(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylateis thereby obtained in the form of a white foam.

4α-Acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,10β-dihydroxy-9-oxo-7β-trifluoromethanesulphonate-11-taxen-13α-yl(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylatemay be prepared in the following manner:

0.54 cm³ of trifluoromethanesulphonic anhydride is added dropwise to asolution, maintained under an argon atmosphere at a temperature in theregion of -35° C., of 1.9 g of4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,7β,10.beta.-trihydroxy-9-oxo-11-taxen-13α-yl(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylatein 20 cm³ of anhydrous dichloromethane and 0.68 cm³ of anhydrouspyridine. The reaction mixture is stirred for 10 minutes at -35° C. and90 minutes at a temperature in the region of -5° C., and 5 cm³ ofdistilled water are then added to it at a temperature in the region of-15° C. After settling has taken place, the aqueous phase is separatedand re-extracted with 2 cm³ of dichloromethane, and the organic phasesare combined, dried over magnesium sulphate, filtered through sinteredglass and concentrated under reduced pressure (0.27 kPa) at atemperature in the region of 40° C. 2.4 g of a yellow oil are therebyobtained, which product is purified by chromatography at atmosphericpressure on 100 g of silica (0.063-0.2 mm) contained in a column 3.2 cmin diameter (eluent: methanol/dichloromethane, 2:98 by volume),collecting 15 cm³ fractions. Fractions containing only the desiredproduct are pooled and concentrated to dryness under reduced pressure(0.27 kPa) at 40° C. for 2 hours. 1.23 g of4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,10-dihydroxy-9-oxo-7-trifluoromethanesulphonate-11-taxen-13α-yl(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylateare thereby obtained in the form of a pale yellow foam.

4α-Acetoxy-2α-benzoyloxy-5β,20-epoxy-1,7β,10β-trihydroxy-9-oxo-11-taxen-13α-yl(2R,4S,5R))-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylatemay be prepared in the following manner:

A solution of 3.95 g of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β-hydroxy-9-oxo-7.beta.,10β-bis(2,2,2-trichloroethoxy)carbonyloxy-11-taxen-13α-yl(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylatein a mixture of 20 cm³ of methanol and 7 cm³ of acetic acid is heatedwith stirring under an argon atmosphere to a temperature in the regionof 60° C., and 2 g of powdered zinc are then added to it. The reactionmixture is then stirred for 15 minutes at 60° C., thereafter cooled to atemperature in the region of 20° C. and filtered through sintered glasslined with Celite. The sintered glass is washed with 2 times 15 cm³ ofmethanol. The filtrate is concentrated to dryness under reduced pressure(0.27 kPa) at a temperature in the region of 40° C. 100 cm³ ofdichloromethane are added to the residue. The organic phase is washedwith 2 times 10 cm³ of saturated aqueous sodium hydrogen carbonatesolution and then with 10 cm³ of distilled water. The organic phase isdried over magnesium sulphate, filtered through sintered glass and thenconcentrated to dryness under reduced pressure (2.7 kPa) at 40° C. 5.57g of a white foam are obtained, which product is purified bychromatography on 300 g of silica (0.063-0.2 mm) contained in a column 6cm in diameter (elution gradient: methanol/dichloromethane, from 0:100to 2:98 by volume), collecting 100 cm³ fractions. Fractions containingonly the desired product are pooled and concentrated to dryness underreduced pressure (0.27 kPa) at 40° C. for 2 hours. 2.52 g of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1,7β,10β-trihydroxy-9-oxo-11-taxen-13α-yl(2R,4S,5R))-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-5-oxazolidinecarboxylateare thereby obtained in the form of a white foam.

4-Acetoxy-2α-benzoyloxy-5β,20-epoxy-1β-hydroxy-9-oxo-7.beta.,10β-bis(2,2,2-trichloroethoxy)carbonyloxy-11-taxen-13α-yl(2R,4S,5R))-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylatemay be prepared under the conditions described in PCT InternationalApplication WO 94/07878 the disclosure of which is incorporated byreference.

The new products of general formula (I) in which Z represents a radicalof general formula (II) manifest significant inhibatory activity withrespect to abnormal cell proliferation, and possess therapeuticproperties permitting the treatment of patients having pathologicalconditions associated with abnormal cell proliferation. The pathologicalconditions include the abnormal cell proliferation of malignant ornon-maligant cells of various tissues and/or organs, comprising, withoutimplied limitation, muscle, bone or connective tissue, the skin, brain,lungs, sex organs, the lymphatic or renal systems, mammary or bloodcells, liver, the digestive system, pancreas and thyroid or adrenalglands. These pathological conditions can also include psoriasis, solidtumours, cancers of the ovary, breast, brain, prostate, colon, stomach,kidney or testicles, Kaposi's sarcoma, cholangiocarcinoma,choriocarcinoma, neuroblastoma, Wilms' tumour, Hodgkin's disease,melanoma, multiple myeloma, chronic lymphocytic leukaemia and acute orchronic granulocytic lymphoma. The new products according to theinvention are especially useful for the treatment of cancer of theovary. The products according to the invention may be used to prevent ordelay the appearance or reappearance of the pathological conditions, orto treat these pathological conditions.

The products according to the invention may be administered to a patientaccording to different dosage forms suited to the chosen administrationroute, which is preferably the parenteral route. Parenteraladministration comprises intravenous, intraperitoneal, intramuscular orsubcutaneous administration. Intraperitoneal or intravenousadministration is more especially preferred.

The present invention also comprises pharmaceutical compositionscontaining at least one product of general formula (I), in a sufficientamount suitable for use in human or veterinary therapy. The compositionsmay be prepared according to the customary methods, using one or morepharmaceutically acceptable adjuvants, vehicles or excipients. Suitablevehicles include diluents, sterile aqueous media and various non-toxicsolvents. Preferably, the compositions take the form of aqueoussolutions or suspensions, injectable solutions which can containemulsifying agents, colourings, preservatives or stabilizers.

The choice of adjuvants or excipients may be determined by thesolubility and chemical properties of the product, the particular modeof administration and good pharmaceutical practice.

For parenteral administration, sterile, aqueous or non-aqueous solutionsor suspensions are used. For the preparation of non-aqueous solutions orsuspensions, natural vegetable oils such as olive oil, sesame oil orliquid petroleum, or injectable organic esters such as ethyl oleate, maybe used. The sterile aqueous solutions can consist of a solution of apharmaceutically acceptable salt dissolved in water. The aqueoussolutions are suitable for intravenous administration provided the pH isappropriately adjusted and the solution is made isotonic, for examplewith a sufficient amount of sodium chloride or glucose. Thesterilization may be carried out by heating or by any other means whichdoes not adversely affect the composition.

It is clearly understood that all the products participating in thecompositions according to the invention must be pure and non-toxic inthe amounts used.

The compositions can contain at least 0.01% of therapeutically activeproduct. The amount of active product in a composition is such that asuitable dosage can be prescribed. Preferably, the compositions areprepared in such a way that a single dose contains from 0.01 to 1000 mgapproximately of active product for parenteral administration.

The therapeutic treatment may be performed concurrently with othertherapeutic treatments including antineoplastic drugs, monoclonalantibodies, immunotherapy or radiotherapy or biological responsemodifiers. The response modifiers include, without implied limitation,lymphokines and cytokines such as interleukins, interferons (α, β or δ)and TNF. Other chemotherapeutic agents which are useful in the treatmentof disorders due to abnormal cell proliferation include, without impliedlimitation, alkylating agents, for instance nitrogen mustards such asmechloretamine, cyclophosphamide, melphalan and chlorambucil, alkylsulphonates such as busulfan, nitrosoureas such as carmustine,lomustine, semustine and streptozocin, triazenes such as dacarbazine,antimetabolites such as folic acid analogues, for instance methotrexate,pyrimidine analogues such as fluorouracil and cytarabine, purineanalogues such as mercaptopurine and thioguanine, natural products, forinstance vinca alkaloids such as vinblastine, vincristine and vendesine,epipodophyllotoxins such as etoposide and teniposide, antibiotics suchas dactinomycin, daunorubicin, doxorubicin, bleomycin, plicamycin andmitomycin, enzymes such as L-asparaginase, various agents such ascoordination complexes of platinum, for instance cisplatin, substitutedureas such as hydroxyurea, methylhydrazine derivatives such asprocarbazine, adrenocortical suppressants such as mitotane andaminoglutethimide, hormones and antagonists such asadrenocorticosteroids such as prednisone, progestins such ashydroxyprogesterone caproate, methoxyprogesterone acetate and megestrolacetate, oestrogens such as diethylstilboestrol and ethynyloestradiol,antioestrogens such as tamoxifen, and androgens such as testosteronepropionate and fluoxymesterone.

The doses used for carrying out the methods according to the inventionare those which permit a prophylatic treatment or a maximum therapeuticresponse. The doses vary according to the administration form, theparticular product selected and features distinctive to the subject tobe treated. In general, the doses are those which are therapeuticallyeffective for the treatment of disorders due to abnormal cellproliferation. The products according to the invention may beadministered as often as necessary to obtain the desired therapeuticeffect. Some patients may respond rapidly to relatively high or lowdoses, and then require low or zero maintenance doses. Generally, lowdoses will be used at the beginning of the treatment and, if necessary,increasingly stronger doses will be administered until an optimum effectis obtained. For other patients, it may be necessary to administermaintenance doses 1 to 8 times a day, and preferably 1 to 4 times,according to the physiological requirements of the patient in question.It is also possible that some patients may require the use of only oneto two daily administrations.

In man, the doses are generally between 0.01 and 200 mg/kg. Forintraperitoneal administration, the doses will generally be between 0.1and 100 mg/kg, preferably between 0.5 and 50 mg/kg and still morespecifically between 1 and 10 mg/kg. For intravenous administration, thedoses are generally between 0.1 and 50 mg/kg, preferably between 0.1 and5 mg/kg and still more specifically between 1 and 2 mg/kg. It isunderstood that, in order to choose the most suitable dosage, accountshould be taken of the administration route, the patient's weight,general state of health and age and all factors which may influence theefficacy of the treatment.

The example which follows illustrates a composition according to theinvention.

EXAMPLE

40 mg of the product obtained in Example 1 are dissolved in 1 cm³ ofEmulphor EL 620 and 1 cm³ of ethanol, and the solution is then dilutedby adding 18 cm³ of physiological saline.

The composition is administered by perfusion over 1 hour by introductionin physiological solution.

We claim:
 1. A taxoid of the formula (I): ##STR12## wherein: Rrepresents an unbranched or branched alkyl radical comprising 1 to 6carbon atoms, an unbranched or branched alkenyl radical comprising 2 to6 carbon atoms, an unbranched or branched alkynyl radical comprising 2to 6 carbon atoms, a cycloalkyl radical comprising 3 to 6 carbon atoms,a cycloalkenyl radical comprising 4 to 6 carbon atoms, an aryl radical,or a 5- to 6-membered aromatic heterocyclic radical;Z represents ahydrogen atom or a radical of the formula (II): ##STR13## wherein: R₁represents a benzoyl radical unsubstituted or substituted with at leastone substituent selected from a halogen atom, an alkyl radicalcomprising 1 to 4 carbon atoms, an alkoxy radical comprising 1 to 4carbon atoms, a trifluoromethyl radical, a thenoyl radical, a furoylradical, or a radical R₂ --O--CO-- in which R₂ represents:an alkylradical comprising 1 to 8 carbon atoms, an alkenyl radical comprising 2to 8 carbon atoms, an alkynyl radical comprising 3 to 8 carbon atoms, acycloalkyl radical comprising 3 to 6 carbon atoms, a cycloalkenylradical comprising 4 to 6 carbon atoms, or a bicycloalkyl radicalcomprising 7 to 10 carbon atoms, these radicals being unsubstituted orsubstituted with at least one substituent selected from the groupconsisting of a halogen atom, a hydroxyl radical, an alkoxy radicalcomprising 1 to 4 carbon atoms, a dialkylamino radical in which eachalkyl portion comprises 1 to 4 carbon atoms, a piperidino radical, amorpholino radical, a 1-piperazinyl radical (unsubstituted orsubstituted at the 4 position with an alkyl radical comprising 1 to 4carbon atoms or with a phenylalkyl radical in which the alkyl portioncomprises 1 to 4 carbon atoms), a cycloalkyl radical comprising 3 to 6carbon atoms, a cycloalkenyl radical comprising 4 to 6 carbon atoms, aphenyl radical (unsubstituted or substituted with at least onesubstituent selected from the group consisting of a halogen atom, analkyl radical comprising 1 to 4 carbon atoms, and an alkoxy radicalcomprising 1 to 4 carbon atoms), a cyano radical, a carboxyl radical,and an alkoxycarbonyl radical in which the alkyl portion comprises 1 to4 carbon atoms; a phenyl or α- or β-naphthyl radical unsubstituted orsubstituted with at least one substituent selected from the groupconsisting of a halogen atom, an alkyl radical comprising 1 to 4 carbonatoms, an alkoxy radical comprising 1 to 4 carbon atoms, and a5-membered aromatic heterocyclic radical; or a saturated heterocyclicradical comprising 4 to 6 carbon atoms, unsubstituted or substitutedwith at least one alkyl radical comprising 1 to 4 carbon atoms; R₃represents an unbranched or branched alkyl radical comprising 1 to 8carbon atoms, an unbranched or branched alkenyl radical comprising 2 to8 carbon atoms, an unbranched or branched alkynyl radical comprising 2to 8 carbon atoms, a cycloalkyl radical comprising 3 to 6 carbon atoms,a phenyl or α- or β-naphthyl radical unsubstituted or substituted withat least one substituent selected from the group consisting of a halogenatom and an alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, alkylthio,aryloxy, arylthio, hydroxyl, hydroxyalkyl, mercapto, formyl, acyl,acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino,dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl,dialkylcarbamoyl, cyano, nitro, and trifluoromethyl radical, or a5-membered aromatic heterocycle comprising at least one heteroatom,identical or different, selected from nitrogen, oxygen or sulphur atomsand unsubstituted or substituted with at least one substituent,identical or different, selected from the group consisting of a halogenatom and an alkyl, aryl, amino, alkylamino, dialkylamino,alkoxycarbonylamino, acyl, arylcarbonyl, cyano, carboxyl, carbamoyl,alkylcarbamoyl, dialkylcarbamoyl, and alkoxycarbonyl radical, whereinfor the substituents of the phenyl, α- or β-naphthyl and aromatichetereocyclic radicals, the alkyl radicals and alkyl portions of theother radicals comprise 1 to 4 carbon atoms, the alkenyl and alkynylradicals comprise 2 to 8 carbon atoms, and the aryl radicals are phenylor α- or β-naphthyl radicals.
 2. The taxoid according to claim 1whereinR represents an alkyl radical comprising 1 to 4 carbon atoms; Zrepresents a hydrogen atom or a radical of the formula (ll) in which R₁represents a benzoyl radical or a radical R₂ --O--CO-- in which R₂represents a tert-butyl radical; and R₃ represents an alkyl radicalcomprising 1 to 6 carbon atoms, an alkenyl radical comprising 2 to 6carbon atoms, a cycloalkyl radical comprising 3 to 6 carbon atoms, aphenyl radical unsubstituted or substituted with at least one, identicalor different, substituent selected from the group consisting of ahalogen atom and an alkyl, alkoxy, dialkylamino, acylamino,alkoxycarbonylamino, trifluoromethyl, 2- or 3-furyl, 2- or 3-thienyl,and 2-, 4- or 5-thiazolyl radical.
 3. The taxoid according to claim 1whereinR represents a methyl radical; Z represents a hydrogen atom or aradical of the formula (II) in which R₁, represents a benzoyl radical ora radical R₂ --O--CO-- in which R₂ represents a tert-butyl radical; andR₃ represents an isobutyl, isobutenyl, butenyl, cyclohexyl, phenyl,2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl, or5-thiazolyl radical.
 4. A process for preparing a taxoid according toclaim 1 wherein an organometallic derivative of the formula (III):

    R--X.sub.1                                                 (III)

wherein R is defined as in claim 1 and X₁ represents a metal atom or anorganomagnesium residue; is reacted with a compound of the formula (IV):##STR14## wherein Z₁ represents a hydrogen atom or a radical of theformula (V): ##STR15## wherein R₁ and R₃ are defined as in claim 1, andeither R₄ represents a hydrogen atom and R₅ represents a groupprotecting the hydroxyl function or R₄ and R₅ together form aheterocycle;to obtain a product of the formula (VI): ##STR16## whereinZ₁ and R are defined as in claim 1; and the protective groupsrepresented by R₅ or R₄ and R₅ are, where appropriate, replaced byhydrogen atoms.
 5. The process according to claim 4, wherein theorganometallic derivative is reacted by working in an inert organicsolvent at a temperature of about -78° to about +30° C.
 6. The processaccording to claim 4, wherein when R₄ represents a hydrogen atom and R₅represents a group protecting the hydroxyl function, comprisingreplacing the R₅ protecting group with a hydrogen atom by using aninorganic or organic acid, or combination thereof, working in an organicsolvent selected from alcohols, ethers, esters, aliphatic hydrocarbons,halogenated aliphatic hydrocarbons, aromatic hydrocarbons, or nitritesat a temperature of about -10° to about 60° C.
 7. The process accordingto claim 4, wherein when R₄ and R₅ together form an oxazolidine ring ofthe formula (VII): ##STR17## wherein R₁ is defined as in claim 1; andR₆and R₇, which may be identical or different, represent a hydrogen atomor an alkyl radical comprising 1 to 4 carbon atoms, an aralkyl radicalin which the alkyl portion comprises 1 to 4 carbon atoms, an arylradical; or alternatively R₆ represents an alkoxy radical comprising 1to 4 carbon atoms, a trihalomethyl radical, or a phenyl radicalsubstituted with a trihalomethyl radical, and R₇ represents a hydrogenatom; or alternatively R₆ and R₇, together with the carbon atom to whichthey are attached, form a 4- to 7-membered ring; comprising replacingthe protecting groups formed by R₆ and R₇ with hydrogen, depending onthe meanings of R₁, R₆ and R₇, in the following manner:a) when R₁represents a tert-butoxycarbonyl radical and R₆ and R₇, which may beidentical or different, represent an alkyl radical, an aralkyl radical,or an aryl radical; or alternatively R6 represents a trihalomethylradical or a phenyl radical substituted with a trihalomethyl radical andR₇ represents a hydrogen atom; or alternatively R6 and R₇ together forma 4- to 7-membered ring; the protecting groups are replaced by treatingthe ester of formula (VI) with an inorganic or organic acid, whereappropriate in an organic solvent selected from an alcohol, to yield theproduct of the formula (VIII): ##STR18## wherein R and R₃ are defined asin claim 1; and the product of formula (VII) is acylated by usingbenzoyl chloride in which the phenyl ring is unsubstituted orsubstituted by thenoyl chloride, furoyl chloride, or a compound offormula (IX):

    R.sub.2 --O--CO--X.sub.2                                   (IX)

wherein R₂ is defined as in claim 1 and X₂ represents a halogen atom ora residue --O--R₂ or --O--CO--O--R₂ ; to obtain a product of the formula(I) in which Z represents a radical of the formula (II); b) when R₁represents an unsubstituted or substituted benzoyl radical, a thenoylradical, furoyl radical, or a radical R₂ O--CO-- in which R₂ is definedas in claim 1; R₆ represents a hydrogen atom, an alkoxy radicalcomprising 1 to 4 carbon atoms, or a phenyl radical substituted with atleast one alkoxy radical comprising 1 to 4 carbon atoms and R₇represents a hydrogen atom; the protecting group formed by R₆ and R₇ isreplaced by a hydrogen atom in the presence of an inorganic or organicacid or combination thereof in a stoichiometric or catalytic amount,working in an organic solvent selected from alcohols, ethers, esters,aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatichydrocarbons at a temperature of about -10° to about 60° C.
 8. Apharmaceutical composition comprising at least one taxoid according toclaim 1 in which Z represents a radical of the formula (II) and at leastone pharmaceutically acceptable product.
 9. The taxoid according toclaim 1, wherein the R₂ 5-membered aromatic heterocyclic radical is afuryl or thienyl radical.
 10. The taxoid according to claim 2, whereinthe halogen atom substituent for the R₂ phyenyl radical is fluorine orchlorine.
 11. The taxoid according to claim 4, wherein X₁ represents alithium atom.
 12. The taxoid according to claim 7, wherein the arylportion of the R₆ or R₇ aralkyl radical is a phenyl radicalunsubstituted or substituted with at least one alkoxy radical comprising1 to 4 carbon atoms.
 13. The taxoid according to claim 7, wherein the R₆or R₇ aryl radical is a phenyl radical unsubstituted or substituted withat least one alkoxy radical comprising 1 to 4 carbon atoms.
 14. Thetaxoid according to claim 7, wherein the trihalomethyl radical is atrichloromethyl radical.
 15. The taxoid according to claim 7, whereinthe halogen atom of X₂ is fluorine or chlorine.
 16. A pharmaceuticalcomposition comprising a taxoid according to claim 1 in which Zrepresents a formula (II) radical and a pharmaceutically acceptablecarrier.